The metabolic syndrome (also known as syndrome X, insulin resistance syndrome), is a clustering of clinical conditions including obesity, dyslipidemia, hyperglycemia and hypertension, that greatly increases an individuals' probability for developing cardiovascular disease and other health problems, such as type-2 diabetes and stroke.
Several organizations, including for example the World Health Organization (WHO), the National Cholesterol Education Program (NCEP), the American Heart Association (AHA) and the National Heart Lung and Blood Institute (NHLBI), have attempted to formulate a definition of the metabolic syndrome, and established a set of criteria for the diagnosis of the disease. In general, the metabolic syndrome is identified by the presence of three or more of the following criteria: abdominal obesity (determined by increased waist circumference with ethnicity-specific cut-off values), elevated triglycerides or treatment for elevated triglycerides, low concentration of HDL-cholesterol or treatment for this condition, elevated blood pressure or treatment for hypertension, and impaired fasting glucose concentration or treatment with a hypoglycemic agent. The presence of just one (or two) of these conditions is not defined as a metabolic syndrome, however any of them increases the risk of developing a more serious disease.
Insulin resistance and compensatory hyperinsulinemia are known to have central etiologic roles in the development of the metabolic syndrome. Overweight and obesity have also been described as central causative components in the development of the syndrome.
Several clinical conditions are thought to be associated with the metabolic syndrome, although not part of its diagnostic criteria. One example is non-alcoholic fatty liver disease (NAFLD). Available data from clinical, experimental and epidemiological studies describe the NAFLD as the hepatic manifestation of the metabolic syndrome. It includes a spectrum of liver damage ranging from pure fatty liver, or steatosis, to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and rarely, progression to cirrhosis. NAFLD is associated with the metabolic syndrome, but can also result from risk factors that do not relate to the syndrome, and may occur, for example, in non-obese and non-diabetic patients.
Several clinical conditions are thought to be complications of the metabolic syndrome, such as pre-diabetes and type-2 diabetes that is noted above.
Treatment of the metabolic syndrome typically combines lifestyle changes and medicinal treatment of the individual components of the syndrome. A combination of medicines is usually required in order to obtain satisfactory results. Common interventions include diet modification, exercise and use of a combination of pharmaceutical agents, such as cholesterol-lowering and blood pressure-lowering agents, to treat risk factors.
Bile acids are steroid acids found predominantly in the bile of mammals. In mammals, the naturally occurring bile acids are C24 carboxylic acids which are formed from cholesterol in the liver. After their biosynthesis, their side chain may be amidated with glycine or taurine to form N-acyl conjugates which are secreted into the bile and stored in the gallbladder. During digestion, bile acids are secreted into the small intestine where they facilitate lipid absorption. The conjugated bile acids are not absorbed during digestion in the proximal small intestine because they are large, ionized molecules that are resistant to deamidation by pancreatic and mucosal carboxypeptidases. Instead, the conjugated bile acids pass to the distal ileum, where they are efficiently absorbed by an active transport system. A small fraction of the bile acids escapes absorption from the ileum and is excreted in the feces.
Synthetic conjugates of bile acids and amino acids have been described. For example, Huijghebaert et al. (1986) “Influence of the amino acid moiety on deconjugation of bile acid amidates by cholylglycine hydrolase or human fecal cultures”, Journal of Lipid Research, 27: 742-752, report about a study of the influence of the chemical structure of the amino acid (or amino acid analogue) moiety of a number of synthetic cholyl amidates on deconjugation by cholylglycine hydrolase from Clostridium pnfnngem. Myher et al. (1975) “Identification of ornithine and arginine conjugates of cholic acid by mass spectrometry”, Can J Biochem, 53:583-590, report about the preparation and mass spectrometry analysis of Nalpha-cholyl-ornithine, -arginine, and -histidine.
U.S. Pat. No. 6,251,428 discloses compositions for pharmaceutical and other uses for preparing clear aqueous solutions containing bile acids which do not form precipitates over selected ranges of pH values of the aqueous solution and methods of making such solutions.
U.S. Pat. No. 7,858,608 discloses farnesoid X receptors (FXR) modulators which can be used for the treatment of cholestatic disorders, in particular to bile acids derivatives wherein the C24 carboxy group is transformed into an amido, carbamido or thiocarbamido group.
US 2005/0260237 discloses a delivery agent for delivering a biologically active agent to a warm-blooded animal that includes a hydrophobic moiety covalently bonded to a hydrophilic moiety. The hydrophobic moiety can include bile acids, sterols, or hydrophobic small molecules. The hydrophilic moiety can include alpha-amino acids, dipeptides or tripeptides, or hydrophilic small molecules. An illustrative delivery agent is Nα-deoxycholyl-L-lysine-methylester. The delivery agent and the biologically active agent are mixed together to form a complex, which is then administered to the animal. These complexes are particularly useful for oral administration of biologically active agents, but other routes of administration may be used.
US 2008/0026077 discloses a method for the delivery of a therapeutic to epithelial cells through the use of a bile acid conjugated to a peptide, the peptide being ionically charged at physiological pH.
There remains a medical need for more effective compositions and methods for treating clinical conditions associated with the metabolic syndrome. There is a further need for novel molecules particularly useful for meeting said medical need.